Peptide beta-turn mimetic compounds and processes for making them

ABSTRACT

The subject invention involves compounds having structure (I), wherein: (a) R1 is hydrogen or alkyl; and R2 is selected from hydrogen, alkyl, aryl, heterocyclyl, carboxy and its esters and amides; or R1 and R2 are attached and are together alkylene or heteroalkylene; (b) R4 is selected from aryl, heteroaryl, and α,β-unsaturated conjugated aryl or heteroaryl; and (c) R5 is selected from hydrogen, alkyl, aryl, and heterocyclyl; and an optical isomer, diesteriomer, or enantiomer thereof; a salt, hydrate, ester, amide or imide thereof. The subject invention also includes libraries of such compounds, and processes for making the subject compounds and libraries.

CROSS REFERENCE

[0001] This application claims priority under Title 35, United StatesCode 119(e) from Provisional Application Serial No. 60/172,823, filedDec. 21, 1999.

FIELD OF THE INVENTION

[0002] The subject invention relates to novel peptide β-turn mimeticcompounds and processes for making such compounds.

BACKGROUND

[0003] In peptides, the β-turn is a subset of the reverse turn and is acommon feature of biologically active peptides and proteins; it iswidely thought to act as a molecular recognition site for manybiological processes. Specific types of β-turns are classified accordingto their geometry.

[0004] The b-turn is defined as any tetrapeptide sequence with a10-membered intramolecularly H-bonded ring, in which the C_(a) ¹ toC_(a) ¹⁺³ distance varies from 4 to 7 Å.

[0005] Depending on f₂, y₂, f₃ and y₃ there are many types of b-turnstructures described in literature. (See: Gillespie et al.,“Conformational Analysis of Dipeptide Mimetics”, Biopoly, Vol. 43,(1997), pp. 191-217; Venkatachalam, Biopolymers, Vol. 6, (1968), pp.1425-36.

[0006] The subject invention compounds are mimetics for β-turn peptides.Such compounds are useful as probes for the study of molecularrecognition events, including enzyme inhibition, cell-cell andcell-matrix interactions. One physical consequence of suchconformational constraint of the subject compounds is a limiting of thenumber of accessible conformational states of the molecules, leading toa better definition of the bioactive conformation of correspondingactive peptides.

[0007] Information regarding β-turn peptides and mimetic compounds canalso be found, for example, in the following references: Ball et al.,“β-Turn Topography”, Tetrahedron, Vol. 49, No. 17 (1993), pp. 3467-3478;Kahn, “Peptide Secondary Structure Mimetics: Recent Advances and FutureChallenges”, SYNLETT, (November 1993), pp. 821-826; Hanessian et al.,“Design and Synthesis of Conformationally Constrained Amino Acids asVersatile Scaffolds and Peptide Mimetics”, Tetrahedron, Vol. 53, No. 38(1997), pp. 12789-12854.

SUMMARY OF THE INVENTION

[0008] The subject invention includes compounds having the structure:

[0009] wherein:

[0010] (a) R1 is hydrogen or alkyl; and R2 is selected from hydrogen,alkyl, aryl, heterocyclyl, carboxy and its esters and amides; or R1 andR2 are attached and are together alkylene or heteroalkylene;

[0011] (b) R4 is selected from aryl, heteroaryl, and α,β-unsaturatedconjugated aryl or heteroaryl; and

[0012] (c) R5 is selected from hydrogen, alkyl, aryl, and heterocyclyl;and an optical isomer, diesteriomer, or enantiomer thereof; a salt,hydrate, ester, amide, or imide thereof.

[0013] The subject invention also includes libraries of such compounds,and processes for making the subject compounds and libraries.

DETAILED DESCRIPTION OF THE INVENTION

[0014] As used herein unless specified otherwise, “alkyl” means ahydrocarbon chain which is branched, linear or cyclic, saturated orunsaturated (but not aromatic), substituted or unsubstituted. The term“alkyl” may be used alone or as part of another word where it may beshortened to “alk” (e.g., in alkoxy, alkylacyl). Preferred linear alkylhave from one to about twenty carbon atoms, more preferably from one toabout ten carbon atoms, more preferably still from one to about sixcarbon atoms, still more preferably from one to about four carbon atoms;most preferred are methyl or ethyl. Preferred cyclic and branched alkylhave from three to about twenty carbon atoms, more preferably from threeto about ten carbon atoms, more preferably still from three to aboutseven carbon atoms, still more preferably from three to about fivecarbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but mayhave two, three, or more, fused or spirocycle hydrocarbon rings.Preferred alkyl are unsaturated with from one to about three double ortriple bonds, preferably double bonds; more preferably they aremono-unsaturated with one double bond. Still more preferred alkyl aresaturated. Saturated alkyl are referred to herein as “alkanyl”. Alkylunsaturated only with one or more double bonds (no triple bonds) arereferred to herein as “alkenyl”. Preferred substituents of alkyl includehalo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio,alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide,arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and arylesters and amides, nitro, and cyano. Also, unsubstituted alkyl arepreferred.

[0015] As used herein, “heteroatom” means a nitrogen, oxygen, or sulfuratom.

[0016] As used herein, “alkylene” means an alkyl which connects twoother moieties, “heteroalkylene” means an alkylene having one or moreheteroatoms in the connecting chain.

[0017] As used herein unless specified otherwise, “aryl” means anaromatic hydrocarbon ring (or fused rings) which is substituted orunsubstituted. The term “aryl” may be used alone or as part of anotherword (e.g., in aryloxy, arylacyl). Preferred aryl have from six to aboutfourteen, preferably to about ten, carbon atoms in the aromatic ring(s),and a total of from about six to about twenty, preferably to abouttwelve, carbon atoms. Preferred aryl is phenyl or naphthyl; mostpreferred is phenyl. Preferred substituents of aryl include halo, alkyl,aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio,amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl,alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides,nitro, and cyano. Also, unsubstituted aryl are preferred.

[0018] As used herein unless specified otherwise, “heterocycle” or“heterocyclyl” means a saturated, unsaturated or aromatic cyclichydrocarbon ring (or fused rings) with one or more heteroatoms in thehydrocarbon ring(s). Preferred heterocycles have from one to about sixheteroatoms in the ring(s), more preferably one or two or threeheteroatoms in the ring(s). Preferred heterocycles have from three toabout fourteen, preferably to about ten, carbon plus heteroatoms in thering(s), more preferably from three to about seven, more preferablystill five or six, carbon plus heteroatoms in the rings(s); and a totalof from three to about twenty carbon plus heteroatoms, more preferablyfrom three to about ten, more preferably still five or six, carbon plusheteroatoms. Preferred heterocycles have one ring, but may have two,three, or more, fused or spirocycle rings. More preferred heterocyclerings include those which are one ring with 5 or 6 carbon plusheteroatoms in the ring with no more than three ring heteroatoms, nomore than two of which are O and S. Still more preferred are such 5- or6-ring atom heterocycles with one or two ring atoms being O or S and theothers being C; or with one, two or three ring atoms being N and theothers being C. Such preferred 5- or 6-ring atom heterocycles arepreferably saturated, unsaturated with one or two double bonds, oraromatic. Such preferred 5- or 6-ring atom heterocycles are preferably asingle ring; or fused with a 3- to 6-ring atom hydrocarbon ring which issaturated, unsaturated with one double bond, or aromatic (phenyl); orfused with another such 5- or 6-ring atom heterocyclic ring.Heterocycles are unsubstituted or substituted. Preferred heterocyclesubstituents are the same as for alkyl.

[0019] As used herein unless specified otherwise, “heteroaryl” means anaromatic heterocycle.

Compounds of the Invention

[0020] The subject invention involves compounds having the followingstructure:

[0021] In structure 2, R1 is hydrogen or alkyl. Preferred R1 is alkylhaving from 1 to about 12 carbon atoms, more preferably from 1 to about6 carbon atoms, more preferably still 1 or 2 carbon atoms. Preferredalkyl R1 is unsubstituted or substituted; preferred substituents includearyl, heterocyclyl, amino, alkylamino, arylamino, hydroxy, alkoxy,aryloxy, thio, alkylthio, arylthio, carboxy and its esters and amides;more preferred substituents include phenyl, naphthyl, and heterocyclylhaving one ring with 5 or 6 ring atoms including 1-3 heteroatoms or twofused rings with 8-10 ring atoms including 1-4 heteroatoms. Morepreferred R1 is hydrogen.

[0022] In structure 2, R2 is selected from hydrogen, alkyl, aryl,heterocyclyl, carboxy and its esters and amides. Alkyl R2 preferably hasfrom 1 to about 8 carbon atoms, more preferably from 1 to about 4 carbonatoms, more preferably still 1 or 2 carbon atoms. Alkyl R2 is preferablyunsubstituted or substituted; preferred substituents include aryl,heterocyclyl, amino, alkylamino, arylamino, hydroxy, alkoxy, aryloxy,thio, alkylthio, arylthio, halo, nitro, cyano, carboxy and its estersand amides; more preferred substituents include phenyl, naphthyl,heterocyclyl having one ring with 5 or 6 ring atoms including 1-3heteroatoms or two fused rings with 8-10 ring atoms including 1-4heteroatoms, hydroxy, C₁-C₆ alkoxy, phenoxy, thio, C₁-C₆ alkylthio,phenylthio, carboxy and its C₁-C₆ esters and amides. Aryl R2 ispreferably phenyl or naphthyl, more preferably phenyl. Aryl R2 ispreferably unsubstituted or substituted; preferred substituents includealkyl, aryl, heterocyclyl, amino, alkylamino, arylamino, hydroxy,alkoxy, aryloxy, thio, alkylthio, arylthio, halo, nitro, cyano, carboxyand its esters and amides; more preferred substituents include C₁-C₆alkyl. Heterocycle R2 preferably is one ring having 5 or 6 ring atomsincluding 1-3 heteroatoms or two fused rings having 8-10 ring atomsincluding 1-4 heteroatoms. More preferred heterocycle R2 is heteroaryl.Heterocycle R2 is preferably unsubstituted or substituted; preferredsubstituents include alkyl, aryl, heterocyclyl, amino, alkylamino,arylamino, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, halo,nitro, cyano, carboxy and its esters and amides; more preferredsubstituents include C₁-C₆ alkyl, phenyl, naphthyl, and heterocyclylhaving one ring with 5 or 6 ring atoms including 1-3 heteroatoms or twofused rings with 8-10 ring atoms including 1-4 heteroatoms.

[0023] R2 is preferably selected from known a-amino acid side-chains,especially those of α-amino acids which commonly occur in nature.

[0024] In structure 2, R1 and R2 may be attached, such attached R1/R2being alkylene or heteroalkylene. Alkylene R1/R2 preferably has from 1to about 6 carbon atoms, more preferably from about 2 to about 4 carbonatoms, more preferably still 3 or 4 carbon atoms. Heteroalkylene R1/R2preferably has from 1 to about 5 carbon atoms, more preferably from 1 toabout 4 carbon atoms, more preferably still 2 or 3 carbon atoms; andpreferably from 1 to about 3 heteroatoms, more preferably 1 or 2heteroatoms, more preferably still 1 heteroatom. Alkylene andheteroalkylene R1/R2 are preferably unsubstituted or substituted;preferred carbon atom substituents include alkyl, aryl, heterocyclyl,amino, alkylamino, arylamino, hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, carboxy, and its esters and amides; more preferred carbon atomsubstituents include hydroxy, C₁-C₆ alkoxy, phenoxy, thio, C₁-C₆alkylthio, phenylthio, carboxy and its C₁-C₆ esters and amides;preferred nitrogen atom substituents include C₁-C₆ alkyl (unsubstitutedor substituted).

[0025] In structure 2, R4 is selected from aryl, heteroaryl, andα,β-unsaturated-conjugated aryl or heteroaryl. Aryl R4 is preferablyphenyl or naphthyl, more preferably phenyl. Aryl R4 is preferablyunsubstituted or substituted; preferred substituents include alkyl,aryl, alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, cyano, carboxyand its esters and amides; more preferred substituents include C₁-C₆alkyl, phenyl, C₁-C₆ alkyoxy, and halo. Heteroaryl R4 preferably is onering having 5 or 6 ring atoms including 1-3 heteroatoms or two fusedrings having 8-10 ring atoms including 1-4 heteroatoms. Heteroaryl R4 ispreferably unsubstituted or substituted; preferred substituents includealkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, cyano,carboxy and its esters and amides; more preferred substituents includeC1-C₆ alkyl, phenyl, C1-C₆ alkoxy, and halo. Conjugated aryl andheteroaryl R4 preferably includes styryl. Conjugated aryl and heteroarylR4 are preferably unsubstituted or substituted; preferred substituentsinclude alkyl, alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, cyano,carboxy and its esters and amides; more preferred substituents includeC₁-C₆ alkyl, phenyl, C1-C₆ alkoxy, and halo.

[0026] In structure 2, R5 is selected from hydrogen, alkyl, aryl, andheterocyclyl. Alkyl R5 preferably has from 1 to about 10 carbon atoms,more preferably from 1 to about 4 carbon atoms, more preferably still 1or 2 carbon atoms. Alkyl R5 is preferably unsubstituted or substituted;preferred substituents include alkyl, aryl, heterocyclyl, amino,alkylamino, arylamino, hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, formyl, alkylacyl, arylacyl, halo, nitro, cyano, carboxy andits esters and amides; more preferred substituents include phenyl,naphthyl, and heterocyclyl having one ring with 5 or 6 ring atomsincluding 1-3 heteroatoms or two fused rings with 8-10 ring atomsincluding 1-4 heteroatoms. Aryl R5 is preferably phenyl or naphthyl,more preferably phenyl. Aryl R5 is preferably unsubstituted orsubstituted; preferred substituents include alkyl, aryl, heterocyclyl,amino, alkylamino, arylamino, hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, formyl, alkylacyl, arylacyl, halo, nitro, cyano, carboxy andits esters and amides; more preferred substituents include C₁-C₆ alkyl,phenyl, and heterocyclyl having one ring with 5 or 6 ring atomsincluding 1-3 heteroatoms or two fused rings with 8-10 ring atomsincluding 1-4 heteroatoms. Heterocycle R5 is preferably one ring having5 or 6 ring atoms including 1-3 heteroatoms or two fused rings having8-10 ring atoms including 1-4 heteroatoms. More preferred heterocycle R5is heteroaryl. Heterocycle R5 is preferably unsubstituted orsubstituted; preferred substituents include alkyl, aryl, heterocyclyl,amino, alkylamino, arylamino, hydroxy, alkoxy, aryloxy, thio, alkylthio,arylthio, formyl, alkylacyl, arylacyl, halo, nitro, cyano, carboxy amidits esters and amides; more preferred substituents include C₁-C₆ alkyl,phenyl, and heterocyclyl having one ring with 5 or 6 ring atomsincluding 1-3 heteroatoms or two fused rings with 8-10 ring atomsincluding 1-4 heteroatoms.

[0027] The subject invention includes optical isomers, diasteromers, andenantiomers of the compounds of structure 2. The subject inventionincludes salts, hydrates, esters, amides, and imides of such compounds.

[0028] As used herein, a “salt” is a cationic salt formed at any acidicgroup (e.g., carboxy group), or an anionic salt formed at any basicgroup (e.g., amino group) on a compound of structure 2. Many salts areknown. Preferred cationic salts include the alkali metal salts, such assodium and potassium, alkaline earth metal salts, such as magnesium andcalcium, and organic salts, such as ammonium. Preferred anionic saltsinclude halides, sulfonates, carboxylates, phosphates, and the like.Salts of addition may provide an optical center where once there wasnone.

[0029] The compounds of the subject invention, and salts thereof, mayhave one or more chiral centers. The invention includes all opticalisomers of the compounds of structure 2 and salts thereof, includingdiasteriomers and enatiomers.

[0030] The subject invention also includes libraries of compounds havingstructure 2. Such libraries can be mixtures of compounds of structure 2or collections of individual compounds of structure 2.

Processes for Making the Compounds

[0031] Another aspect of the subject invention is processes for makingcompounds of structure 2, as generally depicted in Scheme 1.

[0032] Orthogonally protected, resin bound piperazinic acid is used.Deprotection reaction is followed by functionalization of the b-nitrogenatom via the Petasis reaction. Subsequent amide bond formation leads tothe desired inclusion of R4 and R5 substituents. Unblocking of thea-nitrogen, followed by Boc-N-protected a-amino acid coupling,deprotection and cyclizative cleavage, introduces the R2 and R1substituents, and leads to bicyclic product 2.

[0033] In step a, hydroxymethylpolystyrene resin is reacted withN-protected piperazinic acid (3) to bind it to the resin. This reactionis preferably carried out, after swelling the resin in DCM, in thepresence of Ph₃P and DEAD which act as Mitsunobu reagents, in THFsolvent. The resin product is preferably filtered and washed severaltimes using one or more of THF, DCM, and MeOH to purify the product.

[0034] In step b, the protecting group is removed from the β-nitrogen ofthe resin-bound piperazinic acid to produce 4. This is preferablyaccomplished by using a solution of TFA and DCM, preferably about 40%TFA, preferably after swelling the resin reactant in DCM. The resinproduct is preferably filtered and washed several times using DCM and/orMeOH, neutralized, and filtered and washed more to purify it.

[0035] In step c, piperazinic ester resin 4 is reacted with R4-boronicacid and glyoxylic acid. This reaction is preferably carried out in DCMsolvent, preferably after swelling the resin reactant in DCM. The resinproduct is preferably filtered and washed several times using DCM andMeOH, to purify it. This reaction step and purification are preferablyrepeated to increase the yield of the desired product.

[0036] In step d, the resin product from step c is reacted with amineR5-NH₂. Prior to addition of the amine in this step, the resin reactantis preferable swelled using DMF, contacted with HOBt which acts as anactivating agent, followed by contact with DIC which acts as a couplingagent, and is filtered and washed with DMF. After reaction with theamine, the resin product is preferably filtered and washed with DMF.

[0037] In step e, the resin product from step d is contacted withpiperidine which acts as a deprotecting agent. This step is preferablycarried out in a solution of piperidine in DMF, the solution being fromabout 15% to about 30% piperidine. Resulting resin product 5 ispreferably filtered and washed several times in DMF. This step ispreferably repeated to increase the yield of the desired product.

[0038] In step f, resin product 5 is reacted with a N-protected α-aminoacid. This reaction is preferably carried out in the presence of PyBOPwhich acts as a coupling agent, and then a base DiPEA. Prior to addingthe amino acid, the resin reactant is preferably swelled using DMF. Theresin product is preferably filtered and washed several times with DMF.This step is preferably repeated.

[0039] In step g, the protecting group of the α-amino acid of step f isremoved. This is preferably done using a solution of TFA in DCM,preferably about 25% TFA. The resulting resin product is preferablyfiltered and washed several times with DCM and MeOH.

[0040] In step h, the resin product from step g is cleaved from theresin and cyclized to produce product 2. This step is preferably carriedout in a solution of from about 5% to about 20% AcOH in iPrOH, at anelevated temperature of from about 30° C. to about 80° C. for a periodof from about 20 h to about 80 h. The cleaved resin is filtered off andwashed several times, preferably using MeOH. The filtrate and washingsare preferably combined, concentrated, and dried to give 2 as a solid.The solid product is preferably purified by co-evaporating it severaltimes with chloroform, and then drying under vacuum.

[0041] The following non-limiting examples illustrate, in more detail,processes of the subject invention.

EXAMPLE 1

[0042] a) Hydroxymethylpolystyrene resin (1.0 g, 1.44 mmol/g, AdvancedChemtech) is swelled in anhydrous dichloromethane (DCM) (6 mL).Triphenylphosphine (Ph3P) (1.13 g, 4.32 mmole) is dissolved in thisslurry and the heterogeneous reaction is cooled to 0° C. under nitrogen.To this gently stirring slurry is added a tetrahydrofuran (THF) (30 mL)solution of N_(α)-Fmoc-N_(β)-Boc-2-carboxypiperazine 3 (1.95 g, 4.32mmol) and diethylazodicarboxylate (DEAD) (751 mL, 4.32 mmole) over aperiod of 30 minutes. The reaction is allowed to stir for 72 h, at whichpoint the resin is filtered and washed with THF (3×), DCM (3×), MeOH(3×), then multiple, successive and alternating DCM and MeOH washes(standard manner).

[0043] b) Piperazinic resin ester from step a (1.4 g) is swelled in DCM,filtered and treated with a 40% solution of trifluoroacetic acid (TFA)in DCM for 1 h. The resin is filtered and washed with DCM (3×), MeOH(3×), then alternating DCM/MEOH as in (a). The resin bound amine TFAsalt is then neutralized with a 10% solution of diisopropylethylamine(DiPEA) in DCM and re-washed in the standard manner.

[0044] c) The resin ester 4 from step b is swelled in DCM (10 mL) and tothis is added glyoxylic acid (265g, 2.88 mmol) and a boronic acid (2.88mmol) as a solution in MeOH (15 mL). The resulting slurry is agitatedfor 5 h, before filtering the resin and washing with MeOH (3×). Theabove procedure is repeated again for 16 h, after which the resin isagain filtered and washed in the standard manner.

[0045] d) The resin ester from step c is swelled in DMF (5 ml) and tothis is added hydroxybenzotriazole (HOBt) (1.10 g, 7.2 mmol) followed bydiisopropylcarbodiimide (DIC) (907 mg, 7.2 mmol). The reaction isagitated for 3h, after which the resin is washed with dimethylformamide(DMF) (4×). The resin is swelled again in DMF (10 ml), and to thisslurry is added an amine (7.2 mmol). The reaction is allowed to agitatefor 15 h. The resin is filtered and washed with DMF (3×) followed by thestandard manner wash.

[0046] e) The resin ester from step d is treated with 25% piperidine inDMF for 20 min. The resin is filtered and rinsed with DMF (2X) beforerepeating. The resin product is filtered and washed in the standardmanner.

[0047] f) The resin product 5 from step e is swelled in DMF. To this isadded a boc-α-amino acid (Boc-AA) (7.2 mmole),benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) (3.74 g, 7.2 mmole) followed by DiPEA (1.11 g, 8.64 mmole). Thereaction is agitated for 5 h, filtered and rinsed with DMF (3×) in thestandard manner.

[0048] g) The resin product from step f is treated with 25% TFA/DCM for1 h. The resin is filtered and washed.

[0049] h) The resin product from step g is taken up in 10% acetic acidin isopropanol (AcOH/iPrOH) and heated for 16 h at 50° C. The resin isfiltered off and washed several times using MeOH. The filtrate andwashings are combined and concentrated to give an off white solid. Thesolid as co-evaporated several times using chloroform before being driedunder vacuum for 15 h.

EXAMPLES 2-7

[0050] The following non-limiting exemplary compounds are made using theprocess of Example 1 by reacting the indicated boronic acids, amines,and boc-α-amino acids therein:

Example Boronic Acid Amine Amino Acid Product 2 phenylboronic acidisoamylamine Boc-Asp (O-tBu)- 2a OH 3 2-thiopheneboronic mono-Boc-butyl-Boc-Lys(Boc)-OH 2b acid 1,4-diamine 4 benzothiophene-2- 4-aminomethyl-Boc-Tic-OH 2c bornonic acid pyridine 5 4-fluoroboronic acidphenethylamine Boc-Phe-OH 2d 6 2-furylboronic acid benzylamineBoc-Phe-OH 2e 7 2-naphthylboronic aniline Boc-Hyp(OBn)-OH 2f acid

[0051] The above processes of the subject invention are carried outusing solid-support resin. This makes reaction separation andpurification of intermediates and final product amenable to automation.Libraries of compounds of structure 2 are readily prepared using thesubject invention processes. Automation of the preparation of suchlibraries is achieved using equipment known to the skilled combinatorialchemist. Such equipment can be used to make libraries which are mixturesof compounds of structure 2 or collections of individual compounds ofstructure 2 each in an isolated well.

[0052] While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the arts that variouschanges and modifications of the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention.

What is claimed is:
 1. A compound having the structure:

characterized in that: (a) R1 is hydrogen or alkyl; and R2 is selectedfrom hydrogen, alkyl, aryl, heterocyclyl, carboxy and its esters andamides; or R1 and R2 are attached and are together alkylene orheteroalkylene; (b) R4 is selected from aryl, heteroaryl, andα,β-unsaturated conjugated aryl or heteroaryl; and (c) R5 is selectedfrom hydrogen, alkyl, aryl, and heterocyclyl; and an optical isomer,diesteriomer, or enantiomer thereof; a salt, hydrate, ester, amide, orimide thereof.
 2. The compound of claim 1 characterized in that (a) R1is hydrogen or C₁-C₁₂ alkyl; and R2 is selected from hydrogen, C₁-C₈alkyl, phenyl, naphthyl, and heterocyclyl having one ring with 5 or 6ring atoms including 1-3 heteroatoms or two fused rings with 8-10 ringatoms including 1-4 heteroatoms; or R1 and R2 are attached and aretogether C₁-C₆ alkylene or heteroalkylene having 1-5 carbon atoms and1-3 heteroatoms; (b) R4 is selected from phenyl, naphthyl, styryl, andheteroaryl having one ring with 5 or 6 ring atoms including 1-3heteroatoms or 2 fused rings with 8-10 ring atoms including 1-4heteroatoms; (c) R5 is selected from hydrogen, C₁-C₁₀ alkyl, phenyl,naphthyl, and heterocyclyl having one ring with 5 or 6 ring atomsincluding 1-3 heteroatoms or 2 fused rings with 8-10 ring atomsincluding 1-4 heteroatoms.
 3. The compound of claim 2 characterized inthat: (a) R1 is hydrogen or unsubstituted or substituted C₁-C₆ alkyl; R2is selected from hydrogen, unsubstituted or substituted C₁-C₄ alkyl,unsubstituted or substituted phenyl, and unsubstituted or substitutedheteroaryl having one ring with 5 or 6 ring atoms including 1-3heteroatoms; or R1 and R2 are attached and together are unsubstituted orsubstituted C₁-C₄ alkylene or unsubstituted or substituted C₁-C₄heteroalkylene also having one or two heteroatoms; (b) R4 is selectedfrom unsubstituted or substituted phenyl, unsubstituted or substitutedstyryl, and unsubstituted or substituted heteroaryl having one ring with5 or 6 ring atoms including 1-3 heteroatoms; and (c) R5 is selected fromhydrogen, unsubstituted or substituted C₁-C₄ alkyl, unsubstituted orsubstituted phenyl, and unsubstituted or substituted heterocyclyl havingone ring with 5 or 6 ring atoms including 1-3 heteroatoms.
 4. Thecompound of claim 3 characterized in that: (a) alkyl RI substituents arephenyl or heterocyclyl having one ring with 5 or 6 ring atoms including1-3 heteroatoms; (b) alkyl R2 substituents are selected from phenyl,heterocyclyl having one ring with 5 or 6 ring atoms including 1-3heteroatoms, hydroxy, C₁-C₆ alkoxy, phenoxy, thio, C₁-C₆ alkylthio,phenylthio, carboxy and its C₁-C₆ esters and amides; (c) aryl R2substituents are C₁-C₆ alkyl; (d) heterocyclyl R2 substituents areselected from C₁-C₆ alkyl, phenyl, and heterocyclyl having one ring with5 or 6 ring atoms including 1-3 heteroatoms; (e) alkylene andheteroalkylene R1/R2 substituents are selected from C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, phenoxy, thio, C₁-C₆ alkylthio, phenylthio,carboxy and its C₁-C₆ esters and amides; (f) phenyl, heteroaryl, andstyryl R4 substituents are selected from C₁-C₆ alkyl, phenyl, C₁-C₆alkoxy, and halo; (g) alkyl R5 substituents are phenyl or heterocyclylhaving one ring with 5 or 6 ring atoms including 1-3 heteroatoms; (h)aryl and heterocyclyl R5 substituents are selected from C₁-C₆ alkyl,phenyl, and heterocyclyl having one ring with 5 or 6 ring atomsincluding 1-3 heteroatoms.
 5. The compound of claim 3 characterized inthat R1 is hydrogen or alkyl, R1 and R2 are attached, and R4 is aryl,heteroaryl, or α,β-unsaturated conjugated aryl or heteroaryl.
 6. Aprocess for making a compound having the structure:

characterized in that a piperazinic acid ester or resin-ester is used asa reactant.
 7. The process of claim 8 characterized in that theβ-nitrogen of the piperazinic acid ester is functionalized using aboronic acid Mannich-type (Petasis) reaction comprising the followingsteps: (a) hydroxymethylpolystryene resin is reacted with N-protectedpiperazinic acid to bind it to the resin to produce step (a) product;(b) the protecting group is removed from the β-nitrogen of the step (a)product to produce step (b) product; (c) the step (b) product is reactedwith R4-boronic acid and glyoxylic acid to produce (c) product; (d) thestep (c) product is reacted with amine R5-NH₂ to produce step (d)product; (e) the step (d) product is deprotected to produce step (e)product; (f) the step (e) product is reacted with a N-protected α-aminoacid to produce step (f) product; (g) the protecting group of thea-amino acid of the step (f) product is removed to produce step (g)product; (h) the step (g) product is cleaved from the resin and cyclizedto produce the compound.
 8. The process of claim 9 characterized inthat: (a) step (c) comprises swelling the step (b) product in DCM, andcarrying out the reaction in MeOH solvent; (b) step (d) comprisesswelling the step (c) product in DMF, contacting it with HOBt which actsas an activating agent, and contacting it with DIC which acts as acoupling agent; (c) step (f) comprises swelling the step (e) product inDMF, contacting it with PyBOP which acts as a coupling agent, and a baseDiPEA, and then the amino acid; (d) step (h) comprises use of a solutionof 5-20% AcOH in iPrOH.
 9. A library of compounds of any of claims 1, 3,4, 8 or
 9. 10. A library of compounds made using the process of claim 9.